The pancreas is an extremely common site for the development of early neoplasms-noninvasive clonal epithelial expansions. In a minority of persons, these clones of cells serially acquire genetic changes that can lead to an invasive adenocarcinoma. Pancreatic cancer, once invasive, is almost uniformly fatal. The epithelial cells in the advanced stage of this process are very aggressive, seemingly having an innate capability for metastasis that is exhibited rather soon after they invade beyond the duct structure into surrounding tissue. In order to alleviate the dismal prognosis associated with this disease, it is imperative that the process of pancreatic carcinogenesis be recognized and treated prior to invasion. Chemoprevention is the administration of agents (drugs, biologics, and nutrients) to slow progression of, reverse, or inhibit carcinogenesis thereby lowering the risk of developing invasive or clinically significant disease. Understanding the morphology and biology of precursor lesions of invasive pancreatic cancer has therefore become an issue of paramount importance. In the last decade, significant progress has been made in the recognition and appropriate classification of these precursor lesions. Mucinous cystic neoplasms (MCNs), intraductal papillary mucinous neoplasms (IPMNs), and pancreatic intraepithelial neoplasia (PanIN) encompass the three known morphologically distinct precursors to invasive pancreatic cancer.
A large number of case-control and cohort studies have shown that there is a significant clustering of pancreatic cancer in some families. These high-risk inherited pancreatic cancers are estimated to represent about 10% of pancreatic cancers. Five well-known genetic syndromes with known gene defects account for approximately 20% of the families in which there is aggregation of pancreatic cancer. These syndromes include (1) BRCA2, (2) familial atypical multiple mole melanoma (p16/CDKN2A), (3) Peutz-Jeghers Syndrome; (4) HNPCC; and (5) familial pancreatitis. Majority of pancreatic cancers are sporadic and have evidence of widespread chromosomal instability, including a high rate of translocations and deletions. Nearly all (>90%) preinvasive lesions have an early mutation in the K-Ras protein involved in the transmission of growth factor signals. In the middle stages of preinvasive progression >90% of lesions develop inactivation of the CDKN2A (p16) cyclin dependent kinase inhibitor. In later stages most preinvasive lesions also harbor mutations of the TP53 (p53) and in MADH4, the common Smad protein involved in transduction of TGFβ and activin signals. Despite the enormous obvious benefit for chemopreventive agents in pancreatic neoplasia, direct drug investigations for chemopreventive indications have been slow to emerge. A critical factor is the challenge of conducting studies that will define and demonstrate clinical benefit.
Proliferation of pancreatic cancer is regulated through aberrant oncogenic Ras signaling and its effect on cyclin kinase inhibitors such as p27kip1. Previous studies have demonstrated that pharmacologic inhibition of one of the ras signaling pathways, the Raf-MEK-ERK pathway, elicits pancreatic cancer cell cycle arrest through induced expression of p27 (Cancer Res 2005; 65(11):4870-80). Tocotrienols, the chemical form of vitamin E with an unsaturated isoprenoid side chain, are receiving attention as promising dietary supplements for cancer prevention and treatment.
Tocotrienols are the primary form of vitamin E in the seeds of most monocot plants such as palm and cereals such as rice and wheat. The biosynthesis of tocotrienols and tocopherols occur exclusively in photosynthetic organisms and arise from homogentisic acid. Tocotrienols arise from the condensation of homogentisic acid and geranylgeranyl diphosphate while the committed step in tocopherol synthesis is the condensation of homogentisic acid and phytyl diphosphate. Structurally tocopherols and tocotrienols share some resemblance consisting of a common chromanol head and a side chain at the C-2 position however, their side chains distinguish tocopherols and tocotrienols.
While tocopherol has a saturated phytyl tail, tocotrienol possesses an unsaturated isoprenoid side chain. Tocopherols and tocotrienols are further separated into individual compounds assigned by the greek letter prefixes (α, β, γ, δ) depending on the number and position of methyl substitution on the chromanol ring. As reflected in their structural similarity, tocopherols and tocotrienols are well recognized for their antioxidant effect. However, tocotrienols are the group of natural vitamin E compounds with clear and consistent antitumor activity. Semisynthetic tocopherols such as tocopherol succinate have antitumor activity however the bioavailability of the intact compound after oral consumption is poor making it unsuitable for chemopreventive interventions. Structure activity studies of the proapoptotic effects of vitamin E compounds have clearly documented the importance of the unsaturated isoprenoid tail of the vitamin E compounds in their antitumor bioactivity. Furthermore, these studies indicate that decreasing the number of methyl substitutions on the chromanol ring, is associated with increasing antitumor potency.